Electrophysiological properties of NG2 + cells: Matching physiological studies with gene expression profiles

Abstract

NG2+ glial cells are a dynamic population of non-neuronal cells that give rise to myelinating oligodendrocytes in the central nervous system. These cells express numerous ion channels and neurotransmitter receptors, which endow them with a complex electrophysiological profile that is unique among glial cells. Despite extensive analysis of the electrophysiological properties of these cells, relatively little was known about the molecular identity of the channels and receptors that they express. The generation of new RNA-Seq datasets for NG2+ cells has provided the means to explore how distinct genes contribute to the physiological properties of these progenitors. In this review, we systematically compare the results obtained through RNA-Seq transcriptional analysis of purified NG2+ cells to previous physiological and molecular studies of these cells to define the complement of ion channels and neurotransmitter receptors expressed by NG2+ cells in the mammalian brain and discuss the potential significance of the unique physiological properties of these cells.

Architecting the myelin landscape

“…OPCs receive glutamatergic and GABAergic synaptic inputs from axons and express a myriad of other neurotransmitter receptors [32,40], perhaps to inform OPCs of a myelination need. A model often termed “activity-dependent myelination” posits that changes in synaptic inputs to OPCs could serve as an inductive cue, causing OPC differentiation and myelination of the axons providing modified inputs, perhaps even converting axon-OPC synapses into a myelinating sheath (Figure 1A) [41].…”

NG2 Glia: Novel Roles beyond Re-/Myelination

“…Indeed, another feature that makes NG2 glia unique among glial cells is the expression of a large repertoire of typically "neuronal" proteins, including ion channels and neurotransmitter receptors. These comprise Ca 2+ -permeable and impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid (AMPA) and N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors; group I (mGluR1 and mGluR5), group II (mGluR3) and group III (mGluR4) metabotropic glutamate receptors; ionotropic and metabotropic GABA receptors; Ca 2+ -permeable and impermeable nicotinic acetylcholine receptors (nAChRs); muscarinic acetylcholine receptors (mAChRs); ionotropic glycine receptors (GlyRs); adrenergic, dopamine, serotonin and purinergic receptors [78]. The expression of these receptors is not universal in NG2 cell populations (e.g., only 60% of the callosal NG2 cells are able to respond to NMDA [79]), indicating a certain degree of heterogeneity within NG2 glia as regards their potential to sense and respond to changes in neurotransmission.…”

“…The expression of these receptors is not universal in NG2 cell populations (e.g., only 60% of the callosal NG2 cells are able to respond to NMDA [79]), indicating a certain degree of heterogeneity within NG2 glia as regards their potential to sense and respond to changes in neurotransmission. Despite the fact that some of these neurotransmitter receptors (i.e., AMPA and ionotropic GABA receptors) have been shown to mediate neuron-to-NG2 glia synaptic communication, activation of most of them is thought to occur through extrasynaptic mechanisms [48], and is associated with large, widespread intracellular Ca 2+ elevations [78].…”

“…Further, the expression of high levels of "leak" potassium channels and the connection with neurons through conventional synapses make NG2 glia able to sense even small changes in neuronal activity with an extremely high temporal and spatial resolution. Of note, NG2 glia have been reported to detect fine changes of extracellular potassium concentration due to the discharge of a single neuron via the inward-rectifier Kir4.1 potassium channels [78,80]. Similarly, by employing two-photon-based glutamate uncaging to produce very localized and brief release of glutamate onto NG2 glia processes segments, Sun et al [81] showed that small neurotransmitter release events at neuron-to-NG2 cell synapses can be sensed via the generation of local depolarizations and, consequentially, local Ca 2+ signals in NG2 glia processes.…”

“…In this context, intracellular Ca 2+ transients-generated in different spatial domains of NG2 glia depending on the pattern/type of incoming activity (including synaptic and extrasynaptic inputs)-likely serve distinct roles. Namely, large Ca 2+ signals involving the entire cell arborization and soma are particularly apt to induce gene expression changes and global cellular actions such as cell division, differentiation, survival or motility [78]. Conversely, beyond allowing the integration of the synaptic activity received by distinct axons, Ca 2+ transients restricted to specific segments of individual processes may be implicated in more compartmentalized functions, such as the stabilization of contacts between NG2 glia processes and axons [82,83], process motility [31], local protein synthesis [84,85], or secretion.…”